Previous investigation of Utah melanoma pedigrees resulted in the identification of the only major melanoma predisposition gene yet identified, cyclin-dependent kinase inhibitor 2A (CDKN2A or p16) (Cannon Albright et al., 1992; Cannon Albright et al., 1994; Kamb et al. 1994). However, only 20-40% of melanoma high-risk pedigrees have a p16 mutation, suggesting that additional melanoma predisposition genes exist. This is also supported by the existence of studied informative melanoma pedigrees that do not have mutations in the coding region of the p16 gene nor demonstrate linkage to the p16 locus on chromosome 9p21. The goal of this project is to identify additional melanoma predisposition genes through the genotypic characterization of Utah high-risk melanoma pedigrees which do not appear to be due to p16, ARF, or CDK4. This investigation will utilize resources that are unique to the University of Utah to identify non-p16 melanoma predisposition genes. These resources include 1) the Utah Population Database (UPDB), which permits identification and recruitment of numerous, extended high-risk melanoma pedigrees and facilitated investigation of the original Utah high-risk pedigree collection used to identify p16 and 2) a highly focused Familial Melanoma Research Clinic (FMRC) that is devoted to the clinical examination and molecular characterization of at-risk relatives in high-risk melanoma pedigrees. We will identify and sample high-risk melanoma pedigrees, perform a genomic search on the pedigrees with no indication of 9p involvement, and fine map any predisposition regions identified. Identification of melanoma predisposition genes will ultimately increase our ability to appropriately screen high-risk patients, and will suggest additional molecular pathways that may serve as targets for the diagnosis and treatment of melanoma.